Mechanisms of insulin secretion mediated by alpha cells

α细胞介导的胰岛素分泌机制

• 批准号: 10675549
• 负责人: Jonathan E Campbell
• 金额: $ 40.81万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10675549
• 关键词: Agonist; Alpha Cell; Animals; Area; B-Cell Antigen Receptor; B-Lymphocytes; Belief; Beta Cell; Cell Communication; Cell Line; Cell physiology; Cell secretion; Cells; Cellular Stress; Clinical; Compensation; Complement; Cyclic AMP; Data; Development; Diabetes Mellitus; Dimensions; Disease; Endocrine; Environment; Enzymes; Event; Fasting; Functional disorder; GLP-I receptor; Genes; Glucagon; Glucagon Receptor; Glucose; Glucose Intolerance; Goals; Health; Hepatic; High Fat Diet; Homeostasis; Hormones; Human; Hyperglycemia; Hypoglycemia; Impairment; Insulin; Interruption; Intervention; Islets of Langerhans; Ligands; Link; Maintenance; Mediating; Metabolic stress; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Paracrine Communication; Pathogenesis; Pathogenicity; Patients; Pattern; Peptide Receptor; Peptide Signal Sequences; Peptides; Phenotype; Physiological; Plasma; Population; Prevention; Production; Proprotein Convertase 1; Proprotein Convertase 2; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Structure of alpha Cell of islet; System; Testing; Tissues; Transcript; Work; antagonist; blood glucose regulation; cell type; diabetic; diabetic patient; driving force; drug development; effective therapy; experimental study; glucagon-like peptide; glucagon-like peptide 1; glucose production; glucose tolerance; human subject; hyperglucagonemia; impaired glucose tolerance; in vivo; insulin secretagogues; insulin secretion; islet; mouse model; novel; paracrine; pharmacologic; proglucagon; real-time images; receptor; response; therapeutic target; transcriptome sequencing; translational potential; translational study

Mechanisms of insulin secretion mediated by alpha cells Pancreatic islets contain multiple endocrine cells that produce hormones intimately involved in the control of glucose homeostasis. -cells, which secrete insulin, are both the most abundant cell type and the most studied cell type. -cell dysfunction leads to insufficient insulin production and ultimately hyperglycemia, the major pathophysiological phenotype of type 2 diabetes (T2D). -cells are the second most abundant cell type within islets, yet substantially less is known about -cell function or the role of these cells in glucose homeostasis. - cells secrete glucagon, which is canonically described as a hyperglycemic agent and an important counter- regulatory hormone in the prevention of hypoglycemia. -cell dysfunction is described as inappropriate glucagon secretion and is considered to be a driving force for hyperglycemia in T2D. However, glucagon receptors (GCGRs) are expressed on -cells and glucagon is a potent insulin secretagogue. Furthermore, it has been recently proposed that -cells synthesize and secrete glucagon-like peptide 1 (GLP-1), through alternative processing of the proglucagon gene transcript. GLP-1 receptors (GLP-1R) are also expressed on -cells, and GLP-1R agonists are currently available for use in T2D to increase insulin production. This raises the intriguing possibility that - to -cell paracrine interactions control insulin production and ultimately glucose homeostasis. Moreover, this perspective allows for the possibility that the increased glucagon secretion seen in T2D is a compensatory mechanism by which the -cells are attempting to increase -cell insulin production. Based on this, we hypothesize that increased -cell activity in T2D is not pathogenic per se, but rather, it is the interruption of - to -cell communication that results in decreased insulin production and hyperglycemia. Therefore, the overall goal of this project is to understand how -cells regulate -cell function, determine the importance of this relationship for normal glucose tolerance, and identify how severing the key node is pathogenic. We will accomplish this by first understanding the importance of - to -cell communication in the context of -cell function and overall glucose tolerance, and then determining if alterations in this axis occur during the development of -cell dysfunction. We will also define the relative importance of -cell glucagon versus GLP-1 production to delineate why -cells would produce two insulin secretagogues. Similarly, we will identify the importance of GCGR versus GLP-1R in -cells to determine if these are redundant systems or if they have unique roles in control of -cell function. This work will encompass cell lines and primary tissues, utilize novel mouse models, and determine the translational potential by conducting key experiments in human subjects in order to comprehensively understand the importance of - to -cell communication in normal and diabetic environments. Completion of this project will enhance our understanding of -cell function in order to identify how best to therapeutically target this cell type for the treatment of T2D.

α细胞介导的胰岛素分泌机制 胰岛含有多种内分泌细胞，其产生密切参与控制胰岛素分泌的激素。 葡萄糖稳态分泌胰岛素的胰岛β细胞是最丰富的细胞类型，也是研究最多的细胞类型。 细胞类型。胰岛细胞功能障碍导致胰岛素分泌不足，最终导致高血糖， 2型糖尿病（T2 D）的病理生理表型。细胞是第二丰富的细胞类型， 胰岛，但对胰岛细胞功能或这些细胞在葡萄糖稳态中的作用知之甚少。- 细胞分泌胰高血糖素，胰高血糖素被经典地描述为高血糖剂和重要的抗血糖剂， 调节激素在预防低血糖中的作用。胰岛细胞功能障碍被描述为不适当的胰高血糖素 在T2 D患者中，高血糖症的发生主要是由于高血糖素分泌所致，并且被认为是T2 D患者高血糖症的驱动力。然而，胰高血糖素受体 胰高血糖素受体（GCGRs）在胰岛β细胞上表达，并且胰高血糖素是有效的胰岛素促分泌素。此外，它还 最近提出胰高血糖素样肽1（GLP-1）是由胰岛细胞合成并分泌的， 胰高血糖素原基因转录物的加工。GLP-1受体（GLP-1 R）也表达于胰岛β细胞， GLP-1 R激动剂目前可用于T2 D以增加胰岛素产生。这就引出了耐人寻味的 β-细胞与β-细胞的旁分泌相互作用控制胰岛素产生并最终控制葡萄糖稳态的可能性。 此外，这一观点允许T2 D中观察到的胰高血糖素分泌增加是一种可能性。 胰岛β细胞试图增加胰岛β细胞胰岛素分泌的代偿机制。基于 因此，我们假设T2 D中β细胞活性的增加本身不是致病性的，而是干扰了T2 D中β细胞的活性。 导致胰岛素分泌减少和高血糖。因此 本项目的总体目标是了解β细胞如何调节β细胞功能，确定其重要性。 正常葡萄糖耐量的关系，并确定如何切断关键节点是致病的。我们将 要做到这一点，首先要理解在蜂窝环境中蜂窝到蜂窝通信的重要性。 功能和总体葡萄糖耐量，然后确定在此轴中是否发生改变， 发展成胰岛细胞功能障碍。我们还将确定β-细胞胰高血糖素与GLP-1的相对重要性， 生产来阐明为什么β细胞会产生两种胰岛素促分泌素。同样，我们将确定 GCGR与GLP-1 R在β细胞中的重要性，以确定这些是否是冗余系统或它们是否具有 在控制胰岛细胞功能中的独特作用。这项工作将包括细胞系和原代组织，利用新的 小鼠模型，并通过在人类受试者中进行关键实验来确定翻译潜力， 为了全面了解正常人和糖尿病患者中胰岛细胞间通讯的重要性， 环境.完成这个项目将提高我们对胰岛细胞功能的理解， 如何最好地治疗靶向这种细胞类型用于治疗T2 D。